Implants and methods for correcting tissue defects

ABSTRACT

The present invention relates to mosaic implant ( 15 ) comprising a plurality of mosaic plates ( 17 ) connected by a wire or mesh anchoring arrangement ( 9 ). Methods for forming such implants and methods for using said implants for correction of bone and soft tissue defects are described.

RELATED APPLICATION

The present application is a 371 of PCT/SE2011/050264 filed Mar. 10,2011.

FIELD OF THE INVENTION

The invention relates to mosaic implants, methods for making suchimplants and methods for the correction of tissue defects.

BACKGROUND OF THE INVENTION

Bone tissue defects that cannot heal via tissue regeneration can befilled using autograph, allograph or synthetic scaffold materials. Forlarge defects e.g. defects in the cranium or in long bones, healing ofbone defect can be especially difficult. Scaffold strategies involveproviding metal meshes or porous ceramic materials which new tissue cangrow upon and/or into. Current strategies using metal mesh can give riseto problems with unhealed defects due to low new bone formation orinfections. Currently used ceramics are mechanically weak and fragilewhich leads to a high risk of scaffold failure due to low mechanicalstrength. Metal meshes can be shaped in the operating theatre to closelyfit the defect whereas the ceramics cannot be shaped after manufacturingand therefore have to be custom made in advance. To overcome the problemof low bone in-growth of Ti-meshes, coating a Ti-mesh withhydroxylapatite powder has been proposed for the use in revision surgeryin joint replacement. This method increases the bone in-growth butlimits the ability to shape the mesh in the operating theatre as bendingthe wires can cause the powder to fall off and the method has not beentested on other metals than Ti. There is unmet need for an implantsystem that facilitates bone in-growth, has high mechanical strength andhas the ability to be shaped in the operating theatre.

BRIEF DESCRIPTION OF THE INVENTION

The present invention describes a mosaic implant, which can be used as abiomedical implant and which combines a wire or mesh anchoring system (awire anchoring system comprises a plurality of wires, preferablycrossing wires, where none of the wires are joined to each other while amesh comprises at least two crossing wires joined at some or all oftheir intersections) and a biomaterial mosaic element, that can beshaped in the operating theatre and which provides increased combinedbone in-growth and better mechanical properties compared to prior artsystems. The implant comprises a mosaic element that combines at leastone flexible high strength wire or mesh with at least two moulded solidmosaic plates. The invention can be employed for the correction of softtissue defects and hard tissue defects. The biomaterial system can becomposed of resorbable biomaterials and/or stable biomaterials such aspolymers, ceramics and metals. Preferably the implant isosteo-conductive (i.e. can serve as a scaffold on which bone cells canattach, migrate, and grow and divide) or osteo-inductive (i.e. can serveto induce new bone formation), can be shaped in the operating room (OR)and have high mechanical strength. This is satisfied by using a mosaicstructured implant system that combines a biomaterial anchoring system(for example a wire mesh) with a solid biomaterial system into a mosaic.This system has the beneficial effects of a mechanically strong wiremesh and an osteo-conductive and/or osteo-inductive solid part whichmeans that the implant system can be easily shaped in the operation roomby cutting the mesh into the desired geometrical shape and size. Thesolid plates, which are moulded at the intersections of the wires duringmanufacturing of the implant, are composed of an osteo-conductive and/orosteo-inductive material that facilitates bone in-growth onto theimplant system.

Preferably the mesh is formed by intersecting wires to form a flat or adished shape. In one embodiment of the present invention biomaterialmosaic plates are attached to intersections of the wire or mesh with agap between the edge surfaces of adjacent plates. In this way a mosaicstructure comprising wire-supported plates separated by gaps is formed.In another embodiment of the present invention a skin with a thicknesswhich is less than the thickness of the biomaterial mosaic plates isformed between some or all of the mosaic plates. The skin is preferablyfrangible, and may be provided with lines of weakness, to allowselective breaking of it in order to shape the mosaic implant.Non-limiting examples of wires include polymers, shape memory alloys,Ti, Ti alloys (e.g. Ti6Al4V) and stainless steel. In the presentapplication the word “wire” is intended to include filaments made of anysuch material. The biomaterials are preferably mouldable from thechemically bonded ceramic class of materials or a biopolymer,non-limiting examples include Ca-salts like: calcium sulphate, calciumphosphate, calcium silicate, calcium carbonate or combinations thereof.The materials are preferably moulded onto the wires or mesh using anon-aqueous water-miscible liquid or using a mixture of water and anon-aqueous water-miscible liquid, allowed to harden to form a mosaicimplant in a water containing bath and subsequently the mosaic implantis released from the mould. After packing and sterilization the mosaicimplant is ready to be used. The strength of the intersecting wires and,where present, the gaps between the plates are chosen so that a surgeonis able to shape the mosaic implant during an operation in order toadapt its shape to the tissue defect being corrected. The wider the gapbetween the plates the more the surgeon is able to deform the implantand hence produce a three-dimensional shape with complex curves. Howeverwider gaps take longer to fill with bone tissue and in order to overcomethis it problem while still allowing the formation of complexthree-dimensional shapes it is possible to provide an implant withdifferent gap widths between the plates—smaller gaps where the implantis intended to be substantially flat and wider gaps where the implant isintended to be curved.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 a) shows schematically a first embodiment of a mould formanufacturing a mosaic implant in accordance with the present invention;

FIG. 1 b) shows schematically a cross-section though section A-A of themould of FIG. 1 a);

FIG. 2 a) shows schematically the mould shown in FIG. 1 a) after a firststep in a method for manufacturing mosaic implant in accordance with thepresent invention;

FIG. 2 b) shows schematically a cross-section though section B-B of themould of FIG. 2 a);

FIG. 3 a) shows schematically the mould shown in FIGS. 1 a) and 2 a)after a second step in a method for manufacturing mosaic implant inaccordance with the present invention;

FIG. 3 b) shows schematically a cross-section though section C-C of themould of FIG. 2 a);

FIG. 4 a) shows schematically a mosaic implant formed when using themould shown in FIGS. 1-3 in a method for manufacturing mosaic implant inaccordance with the present invention;

FIG. 4 b) shows schematically a cross-section though section D-D of themosaic implant of FIG. 4 a);

FIG. 5 a) shows schematically a second embodiment of a mould formanufacturing a mosaic implant in accordance with the present invention;

FIG. 5 b) shows schematically a cross-section though section V-V of themould of FIG. 5 a);

FIG. 6 a) shows schematically the mould shown in FIG. 5 a) after a firststep in a method for manufacturing mosaic implant in accordance with thepresent invention;

FIG. 6 b) shows schematically a cross-section though section VI-VI ofthe mould of FIG. 6 a);

FIG. 7 a) shows schematically the mould shown in FIGS. 5 a) and 5 a)after a second step in a method for manufacturing mosaic implant inaccordance with the present invention;

FIG. 7 b) shows schematically a cross-section though section VII-VII ofthe mould of FIG. 6 a); and,

FIG. 8 a) shows schematically a mosaic implant formed when using themould shown in FIGS. 5-7 in a method for manufacturing mosaic implant inaccordance with the present invention;

FIG. 8 b) shows schematically a cross-section though section VIII-VIIIof the mosaic implant of FIG. 8 a);

FIG. 9 a) shows schematically a third embodiment of a mould formanufacturing a mosaic implant in accordance with the present invention;

FIG. 9 b) shows schematically a cross-section though section IX-IX ofthe mould of FIG. 9 a);

FIG. 10 a) shows schematically a mosaic implant formed when using themould shown in FIGS. 9 a)-9 b) in a method for manufacturing mosaicimplant in accordance with the present invention;

FIG. 10 b) shows schematically a cross-section though section X-X of themosaic implant of FIG. 10 a);

FIG. 11 shows schematically a cross-section though a further mould formanufacturing a mosaic implant in accordance with the present invention;

FIGS. 12 a)-12 d) show axial CT-scans (FIGS. 12 a) and 12 c)) and3D-formatted CT-scans (FIGS. 12 b) and 12 d)) showing a mosaic implantcovering the cranial bone defect in patient no 1 directly after surgery(FIGS. 12 a) and 12 b)) and 3 months later (FIGS. 12 c) and 12 d)); and,

FIGS. 13 a)-13 d) show axial CT-scans (FIGS. 13 a) and 13 c)) and3D-formatted CT-scans (FIGS. 13 b) and 13 d)) showing a mosaic implantcovering the cranial bone defect in patient no 2 directly after surgery(FIGS. 13 a) and 13 b)) and 3 months later (FIGS. 13 c) and 13 d)).

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of a method of manufacturing a mosaic implant inaccordance with the present invention a mould 1 of depth D is usedwhich, as shown in FIGS. 1 a) and 1 b), comprises a plurality ofcavities 3 of depth d, each of which has the shape of a mosaic plate.The depth d of the cavities and the thickness of the resulting mosaicplate is less than the depth D of the mould. Each cavity 3 has a closedbottom end 3′ which is closed by the floor 4 of the mould 1 and is openat the opposite open end 3″ to allow filing of the cavity 3.

Floor 4 does not have to be permanently attached to mould but may, forexample, be a surface which the mould is in contact with duringmanufacturing of the implant and which can be removed after moulding tofacilitate release of the implant from the mould Preferably each cavityand thus each mosaic plate subsequently formed in it has a regular shapesuch as a triangle, a square, a rectangle, a pentagon, a hexagon (asshown in FIGS. 1-4) etc with straight sides. Preferably all the cavitieshave the same shape. In the event that the shapes of cavities are notthe same then adjacent cavities are preferably given complementaryshapes such the cavities can be arranged in patterns with no overlappingand if desired can have substantially equal gaps between adjacent edges.The maximum width of each cavity and thus each mosaic plate is w andpreferably the maximum width w of each cavity is greater than its depthd. Preferably w is between 2 and 20 millimeters, more preferably between3 and 15 mm and even more preferably between 4 and 10 mm. Preferably dis between 10% and 150% of w, more preferably between 20% and 130% of wand most preferably between 50% and 130% of w. Each cavity is separatedby a wall 5 of thickness t in the mould from its adjacentcavity/cavities. Wall thickness t in the mould leads to a gap of nominalthickness t between adjacent plates in the implant, is preferably lessthan 5 mm, more preferably less than 3 mm and most preferably less than2 mm as the smaller the gap is then the easier it is for bone to growand fill the gap between the mosaic plate. However the gap should not betoo small as that will prevent adequate movement of the mosaic plateswith respect to each other—a small gap means that after only a smalldeformation the walls of adjacent mosaic plates will collide and preventthe desired further shaping of the implant. In other words, having alarger gap allows the implant to be deformed more before adjacent platescontact each other, but the larger gaps between plates also take alonger time to fill with bone tissue or indeed may be impossible for thebone cells to bridge. It is of course possible to have different sizedgaps between cavities if the implant is intended to have regions whichwhile be substantially flat and other regions which will be formed intothree-dimensional shapes. Each wall 5 between adjacent cavities 3 ispierced by at least one narrow, wire-retaining channel 7, 7′ of widthww. These wire-retaining channels 7 are intended to receive and retainduring the casting process the wires of similar width ww used to form awire or mesh anchoring arrangement in the implant which maintains themosaic plates in relationship to each other. An anchoring arrangement ispreferably in the form of a mesh structure of crossing wires if the sizeof the implant is sufficiently large enough that it can accommodate amesh structure. It is conceivable that with narrow, elongated implantsthe wires do not cross but are substantially parallel or that they onlycross at a shallow angle and hence may only intersect in a portion ofthe cavities. Preferably the channels 7 running in a first directionhave a depth d1 while channels 7′ running in another direction, forexample an orthogonal direction, have a depth d2 which shallower by adistance which is the same as, or less than the diameter of the wire(see below) used to form the mesh, i.e. d1>d2≧(d1-ww) so that crossingwires are close to each other or in contact with each other. In thisembodiment of the invention the wires are arranged in a grid in whicheach wire is substantially parallel to its neighbouring wire(s) in thesame plane and is crossed by, and in contact with, at least oneperpendicular wire in a different plane. Preferably the wires are spacedsuch that each cavity is crossed by two substantially parallel wiresrunning in a first direction and two wires running in a non-paralleldirection e.g. the perpendicular direction. In another embodiment of theinvention, not shown, each cavity is only crossed by one wire in thefirst direction and one wire in the perpendicular direction. This meansthat the subsequently formed implant can be lighter and more easilyformed. It is also conceivable to have a plurality of wires which runsubstantially parallel in one direction through the cavity but which arecrossed by a less number of wires, e.g. a cavity could have two parallelwires crossed by a single perpendicular wire. Other arrangements such asthree wires crossing at 120° are also conceivable.

While the cavities have been shown with vertical walls 5, it is ofcourse possible to have walls sloping such that the width across anysection of the bottom closed end of each cavity is smaller than thewidth of the corresponding section of the open end of the cavity inorder to form release slopes which aid releasing of the moulded productfrom the mould. Appropriately sloping walls also enable the implant tobe deformed into deeper concave shapes without the edges of adjacentmosaic plates coming into contact with each other than otherwise ispossible with vertical walls.

FIGS. 2 a) and 2 b) shown the mould 1 in a first step in a method tomanufacture a mosaic implant. In this step a wire mesh 11 is formed ofoverlapping wires 9, preferably of width or diameter ww so that they fitsnugly in the wire-retaining channels in order to hold them in placeduring manufacturing and to reduce prevent leakage of cement aroundthem. A wire is placed in, and preferably extends from end to end of,each of the channels. Preferably the channels 7 are arranged such thatwhen the wires are arranged in them the central plane of the resultingwire mesh 11 lies on the central plane of the mould 1. This gives theadvantage that when the mosaic implant is formed it is substantiallysymmetrical about the central plane of the wire mesh which means it isequally easy to make concave and convex adjustments to its shape.However in the event that it is desired to have an implant which is tobe dished in only one direction, e.g. only convex then the wire mesh canbe positioned further away from the central plane of the cavities toallow more bending in the desired direction before adjacent plates comeinto contact with each other.

FIGS. 3 a) and 3 b) shows the mould following a moulding step in themethod for manufacturing a mosaic implant. In this step the cavities 3are filled with a non-aqueous, hydraulic cement composition 13 whichcomprises a non-aqueous mixture of (a) a Ca-salt precursor powdercomposition, and (b) non-aqueous water-miscible liquid. This cementcomposition is moulded onto the wire mesh 11 and allowed to harden, in awet to moist environment. The water in the environment displaces thenon-aqueous water-miscible liquid from the hydraulic cement and allowsthe cement to harden. Preferably the temperature and amount of water inthe environment are adapted so that the hardening process takes at least24 hours as this leads to a strong product. Preferably before the cementhas hardened fully, any excess cement composition 13 present in thewire-retaining channels 7, 7′ is removed.

FIG. 4 a) shows schematically a mosaic implant 15 formed when using themould shown in FIGS. 1-3 after it has been released from the mould 1.Mosaic implant 15 comprises a plurality of mosaic plates 17 each joinedby wires 9 to adjacent mosaic plates while being separated from them bya gap 10 of width t. FIG. 4 b) shows schematically a cross-sectionthough section D-D of the mosaic implant of FIG. 4 a).

In a further embodiment of a method of manufacturing an implant inaccordance with the present invention a mould 21 of depth D is usedwhich, as shown in FIGS. 5 a) and 5 b), comprises a plurality ofcavities 23 of depth d, each of which has the shape of a mosaic plate.The depth d of the cavities is less than the depth D of the mould. Eachcavity 23 has a closed bottom end 23′ which is closed by the floor 24 ofthe mould 21 and is open at the opposite open end 23″ to allow filing ofthe cavity 23. Each wall 25 between adjacent cavities 23 is pierced byat least one narrow, wire-retaining channel 27, 27′ of width ww. In thisembodiment first channels 27 running in a first direction piece twoopposite walls of the cavity at a depth d1 while second channels 27′ arealigned at an angle of 60° with respect to the first channels at a depthd2 which shallower by a distance which is the same as, or less than thediameter of the wire subsequently used to form the anchoring arrangementin the implant which maintains the mosaic plates in relationship to eachother. These second channels piece two different opposing walls of eachcavity. A third set of channels 27″ is provided at an angle of 120° tothe first set of channels 27 and at a depth of d3, and these piece theremaining two opposing walls of each hexagonal cavity. Thus in thisembodiment of the invention the wires are arranged in a grid in whicheach wire is parallel to its neighbouring wire(s) and is crossed by atleast two other wires which respectively make an angle of +60° and −60°with it. Preferably the wires are spaced such that each cavity wall ispierced by a pair of parallel wires. In another embodiment of theinvention, not shown, each cavity wall is only pierced by one wire inthe first direction and one wire in the perpendicular direction. Thismeans that the subsequently formed implant can be lighter and moreeasily formed but at the cost of reduce strength and stability.

FIGS. 6 a) and 6 b) shown the mould 21 in a first step in a method tomanufacture a mosaic implant. In this step a wire mesh 31 is formed ofoverlapping wires 29, preferably of width or diameter ww so that theyfit snugly in the wire-retaining channels.

FIGS. 7 a) and 7 b) shows the mould following a moulding step in themethod for manufacturing a mosaic implant. In this step the cavities 23are filled with a non-aqueous, hydraulic cement composition 33. Thiscement composition is moulded onto the wire mesh 31 and allowed toharden, in a wet to moist environment. The water in the environmentdisplaces the non-aqueous water-miscible liquid from the hydrauliccement and allows the cement to harden. Preferably the temperature andamount of water in the environment are adapted so that the hardeningprocess takes at least 24 hours as this leads to a strong product.Preferably before the cement has harden fully, any excess cementcomposition 33 present in the wire-retaining channels 27, 27, 27′″ isremoved.

FIG. 8 a) shows schematically a mosaic implant 35 formed when using themould shown in FIGS. 5-7 after it has been released from the mould 21.Mosaic implant 35 comprises a plurality of mosaic plates 37 each joinedby wires 29 to adjacent mosaic plates. FIG. 8 b) shows schematically across-section though section VIII-VIII of the mosaic implant of FIG. 8a).

FIGS. 9 a) and 9 b) show an example of a mould 41 for use in yet anotherembodiment of a method for manufacturing a mosaic implant in accordancewith the present invention. In this embodiment of the invention it isdesired to provide a bridging skin of cement material between adjacentmosaic plates. This skin preferably has a thickness s which is less thanthe thickness of the mosaic plates. Preferably it is more than 0.5 mmand less than 5 mm thick and is intended to strengthen the mosaicimplant between mosaic plates. As such a skin would prevent the implantfrom being shaped, the skin is preferably made thin enough so that, ifrequired, it can be broken or cut by a user in selected regions beforebeing attached to a patient. By just breaking or cutting the skin of theimplant at the places necessary to allow the implant to be deformed itis possible to form the implant to the desired shape while maintainingmost of the increased strength provided by the skin. The skin can beformed by sinking the tops of the walls 45 between the cavities by adepth from the top surface of the mould 43 which is the same as thedesired thickness of the skin. The tops of the walls may be providedwith a ridge 47, preferably pointed, which causes local thinning in thesubsequently formed skin. Wire-retaining channels are provided asnecessary and once the wires have been placed in the channels the mouldis filled with cement and allowed to set as before. In the event thatwires are positioned at a depth which is lower than the desired bottomsurface of the skin, spacer material can be provided above the wires toprevent excess cement material from filling the gap between the wiresand the bottom surface of the skin.

FIG. 10 a) shows schematically from below a mosaic implant 55 formedwhen using the mould shown in FIGS. 9 a) and 9 b) after it has beenreleased from the mould 41. Mosaic implant 55 comprises a plurality ofmosaic plates 57 each joined by wires 49 and skin 61 of thickness s toadjacent mosaic plates. FIG. 10 b) shows schematically a cross-sectionthough section X-X of the mosaic implant of FIG. 10 a). The part of theskin 61 where the ridges in the mould were placed is locally thinned,forming lines of weakness 63 which aid in fracturing the skin 61 whendeformation of the implant is required.

In another embodiment of the present invention a mosaic implantcomprises a plurality of mosaic plates, some of which are joined to oneor more neighbouring mosaic plates by a skin and some of which areseparated from one or more neighbouring plates by a gap (shown by dashedlines 65 in FIG. 10 a).

Other moulding methods may be used to form a mosaic implant inaccordance with the present invention. For example, as shownschematically in FIG. 11, an interconnecting mesh 101 (or at least onewire) is placed on the exposed surface 103 of a first mould half 105comprising a plurality of cavities 107 of depth d1 separated by walls109. First mould half 105 is supported in a frame 111. First mould half105 is provided with an excess amount of cement composition 113 (shownby dashed lines) which not only fills the cavities 107 and covers themesh (or wire(s)) but also extends away from the exposed surface of thefirst mould half 105. A second mould half 115, which preferably hascavities 108 of depth d2 arranged as a mirror-image of the first mouldhalf, is subsequently put on top of the mesh and compressed toward thebottom mould to allow moulding of mosaic plates around theinterconnecting mesh. Second mould half 113 may be supported on abacking plate 117. The excess amount of cement composition should besufficient to fill the cavities in the second mould half and should bepositioned to be able to fill the second mould half. Excess cement isremoved after the mould halves have been united and preferably beforehardening of the cement. Hardening of the cement may be achieved byadding moisture via holes 119, each hole being connected to eachmoulding cavity within the mould. Holes 119 are also suitable forallowing excess cement to leave the mould.

The depths of the cavities in each mould half do not have to be thesame. If they are different then the mesh or wire(s) will not bearranged on the central plane of the resulting implant which, ifdesired, will allow the implant to be used with the exposed mesh orwires further away from the skin of the patient and thus less likely tobe damaged in the event of an accident.

The minimum number of cavities in each mould is two and there is nolimit to the maximum number of cavities. The minimum number of wires isone, but preferably wires are at least provided as pairs of parallelwires to provide stability in the plane passing though the longitudinalaxes of each pair of parallel wires.

In all embodiment of the present invention, depending on the compositionof the cement, the hardening of the cement can be performed at reduced,or normal or elevated temperature, and in humid or wet environment. Themould may be may of any dimensionally-stable material which do not reactnegatively with the cement or mesh/wires. If the mould material iswater-permeable it may assist in hardening of the cement.

There are three preferred options regarding the cement moulding:

-   -   1. Use (a) a Ca-salt precursor powder composition, and (b)        non-aqueous water-miscible liquid. In this case the setting        needs to be in a wet environment in order to initiate the        hardening.    -   2. Use (a) a Ca-salt precursor powder composition, and (b) a        mixture between water and a non-aqueous water-miscible liquid.        Setting will initiate automatically but for final hardening a        wet environment is needed.    -   3. (a) a Ca-salt precursor powder composition, and (b)        water-based liquid. Hardening is initiated upon mixing. It is        not necessary to perform hardening in a wet environment but        hardening could be in a wet environment.

The Ca-salt precursor composition may comprise one or more Ca-saltsselected from the group consisting of anhydrous dicalcium phosphate,dicalcium phosphate dihydrate, octacalcium phosphate, α-tricalciumphosphate, β-tricalcium phosphate, amorphous calcium phosphate,calcium-deficient hydroxyapatite, non-stoichiometric hydroxyapatite,tetracalcium phosphate and monocalcium phosphate monohydrate (MCPM),anhydrous monocalcium phosphate, phosphoric acid, pyrophosphoric acid,calcium sulphate (alfa or beta, preferably alfa) or calcium silicate(tricalciumsilicate, dicalciumsilicate or monocalcium silicate), calciumcarbonate (aragonite, vaterite, calcite or amorphous) or combinationsthereof.

In a first embodiment of the invention a non-aqueous water-miscibleliquid may be used in preparing the pastes. Possible liquids includeglycerol and related liquids compounds and derivates (substances derivedfrom non-aqueous water-miscible substances), substitutes (substanceswhere part of the chemical structure has been substituted with anotherchemical structure) and the like. The purpose of the non-aqueouswater-miscible liquid is to give a longer working time during themoulding of the mosaic, because if the material starts to set then it isimpossible to accurately achieve the mosaic shape.

Certain alcohols may also be suitable for use as such a liquid.Preferably the liquid is selected from glycerol, propylene glycol,polypropylene glycol), poly(ethylene glycol) and combinations thereof.The composition may also include agents that facilitate a fast diffusionof water into the paste in situ, preferably non-ionic surfactants likePolysorbates. The amount of surfactant is preferably between 0.01 and 5wt % of the powder composition, most preferably 0.1-1 wt %.

In an alternate embodiment of the present invention the precursor powdercomposition is chosen to obtain a setting time above about 30 minutesand the liquid can then be water-based or water-containing In this casethe liquid can be pure water. In some formulations salts may bedissolved into the liquid to obtain a fast or slower setting, e.g.Citric acid, H₃C₆H₅O₇, Disodium pyrophosphate_Na₂H₂P₂O₇, Sulfuric acid,H₂SO₄, phosphoric acid H₃PO₄. The hardening can then be performed in adry environment.

The compositions may also include porogens to give a macroporous endproduct to facilitate fast resorption and tissue in-growth. The poresgive a good foundation for bone cells to grow in. The porogen mayinclude sugars and other fast-resorbing agents. The amount of porogen issuitably 5 and 30 wt % of the powder composition. This is regardless ofwhether the composition chosen above is premixed or not.

The compositions may also include a non-toxic gelling agent to enhancecohesiveness and washout resistance. The gelling agent may includecollagen, gum, gelatin, alginate, cellulose, polyacrylic acid (e.g. PAA,PAMA), neutral polyacrylic acid (e.g. Na-PAA, Na-PAMA acid), HPMC, HMCand CMC and combinations thereof. The amount of gelling agent preferablyrepresents between 0.1 wt % and 10 wt % of the powder composition, morepreferably between 0.1 wt % and 2 wt %. This is regardless of whetherthe composition chosen above is premixed or not.

In all cement compositions selected above the precursor powder to liquidratio should preferably be within the range of 1 and 10 as this givesoptimal results. The mean grain size of the precursor powder ispreferably below 100 micrometer, and more preferably below 30 micrometeras measured in the volumetric grain size mode. Smaller grain sizes givehigher mechanical strength than larger grain sizes. However for theembodiment of the invention containing porous granules the granule sizemay be larger but preferably is still below 500 micrometer. Normallygranules do not participate in the setting reaction of the paste. Theyare added as ballast to the material and the presence of pores gives abetter biological response to the material. Preferably, at least some ofthe pores in a granule should be large enough for cells to enter intothe granule, normally above at least 10 microns Inevitably there willalso be smaller pores in the granules but they are of less importancefor the cell integration.

In another embodiment of a method of manufacturing an implant inaccordance with the present invention, in the moulding step anon-aqueous, hydraulic cement composition which comprises a non-aqueousmixture of (a) a Brushite- or Monetite-forming calcium phosphate powdercomposition, and (b) non-aqueous water-miscible liquid, is moulded ontothe wire mesh and allowed to harden in a wet to moist environment.

In another embodiment of a method of manufacturing an implant inaccordance with the present invention in the moulding step anon-aqueous, hydraulic cement composition which comprises a non-aqueousmixture of (a) a non-hydrated powder composition comprising porousβ-tricalcium phosphate (β-TCP) granules and at least one additionalcalcium phosphate powder, and (b) non-aqueous water-miscible liquid, ismoulded onto the wire mesh and allowed to harden in a wet to moistenvironment. An example of a wet environment is a water bath. An exampleof a moist environment is a chamber where the relative humidity is 100%.Optionally, hardening of the cement material can be performed atreduced, or normal or elevated temperature, combined with a humid, i.e.a relative humidity over 50%, environment or wet environment.

In an alternate embodiment, the precursor powder composition is basic(apatitic) and comprises (a) a basic calcium phosphate componentcomprising porous β-TCP granules and tetra calcium phosphate (TTCP)and/or amorphous calcium phosphate, and (b) an acidic phosphate,non-limiting examples of which include monocalcium phosphate monohydrate(MCPM), anhydrous monocalcium phosphate, phosphoric acid, pyrophosphoricacid or combinations thereof. The components of the apatitic precursorpowder compositions are chosen such that (i) the pH of the cement pasteduring setting is higher then 6; and (ii) the end-product of the settingreaction comprises amorphous calcium phosphate hydrate, hydroxyapatite,ion-substituted hydroxyapatite, or combinations thereof.

Once the cement has hardened the cement and wire construction can beremoved form the mould, any unwanted cement, for example cement that hasfastened onto the wires between the hexagonal plates 15, removed and theimplant packaged and sterilized.

Optionally the cement and wire construction of the implant system of thepresent invention could be exposed to pressure during hardening, forexample by pressing an inverse mould against the cement, in order toobtain a stronger end product.

Optionally the implant system of the present invention can be combinedwith drugs to form a drug delivery system. Examples of drugs areanti-inflammatory, antibiotics, pain-killers, anti cancer drugs, bonegrowth promoting agents, fibroblast growth factors and bisphosphonates.These drugs can be delivered by using porous components in the implantsystem, e.g. porous wires or porous cement or porous granules or aporous coating, and introducing the drugs into the pores of the porouscomponent.

The implant system can be attached to the host tissue via sutures and/orplates and screws and/or clamps or any other fixing means.

The implant system can be used in tissue replacements (bone and softtissue replacement) and in veterinary medicine. For soft tissuereplacement the mosaic structure is preferably composed of polymericmaterials, preferably resorbable polymers. For hard tissue the mosaicsystem is preferable composed of metal wires and ceramic solids,preferably of metal wires and resorbable ceramics. In the event that thepatient is still growing it is appropriate to use resorbable materialsfor the wires and/or the mosaic plates. Suitable resorbable polymers arePolydioxanone, poly L-lactic acid, and polyglycolic acid.

The implant system may also optionally be combined with an injectablebiomaterial or drug delivery vehicle that guides the tissue in-growthinto the gaps between the plates in the system.

EXPERIMENTAL EXAMPLE 1

A mosaic implant was manufactured using the manufacturing methoddescribed above using premixed acidic calcium phosphate cement mouldedonto Ti wires. The clinical use of this example of a mosaic implant wasfor the restoration of a large cranial defect. Wires were placed in themould which was then filled with the premixed acidic calcium phosphatecement and allowed to harden in water for 48 hours at 20 degrees C.

The premixed acidic calcium phosphate cement consisted ofbeta-tricalcium phosphate, mono calcium phosphate monohydrate andglycerol. The beta-tricalcium phosphate and mono calcium phosphatemonohydrate was mixed in a molar ratio of 1:1 and the glycerol was addedto the powder to obtain a powder:liquid ratio of 3.9:1 [g/ml]. Thecement was thoroughly mixed until a homogenous paste was formed.

After hardening the cement was found to consist of mainly the two phasesbrushite (CaHPO₄-2H₂O) and monetite (CaHPO₄)-however some calciumpyrophosphate (Ca₂O₇P₂) was also found.

The mosaic implant was released from the mould, packaged and steamsterilized. The manufactured mosaic structure was evaluated clinically.

Clinical Evaluation

Patient no 1: A 22-year old patient with a parietal cranial bone defectmeasuring 40×40 mm was operated on. The defect was exposed through alocal cranial skin flap. A sterilized mosaic implant with original sizeof 100×100 mm was cut using a wire cutter and adjusted to a size ofapproximately 45×45 mm. The mosaic implant was fitted into the defect,which required cutting away small amounts of adjacent cranial bone toensure a good fit. The periphery of the defect was formed to make aledge which supported the implant and the implant was subsequentlyclamped to the ledge by titanium plates and screws. The patientdemonstrated no local or systemic side effects and could leave thehospital the day after surgery. A postoperative CT-scan (see FIGS. 12 a)and 12 b)) demonstrated the implant in perfect position covering theoriginal bone defect. The clinical and radiological follow-up made 3months after surgery revealed a well-tolerated implant without signs ofinfection, inflammation or penetration through the skin. The implant wasstill intact without resorption at this early time-point as demonstratedby CT-scans shown in FIGS. 12 c) and 12 d)).

Patient no 2: A 53-year old smoking patient had a large temporal cranialbone defect measuring 80×90 mm. The patient was previously extensivelyoperated on due to the complex craniofacial trauma and has sufferedprevious implants that failed due to infections and penetration throughthe skin. The bone defect was exposed through a standard bi-coronarcranial skin flap. The soft tissue covering the defect was mainlyfibrotic. A sterilized mosaic implant with original size of 100×100 mmwas cut using wire cutters and adjusted to a size of approximately 85×95mm. The mosaic implant was fitted into the defect by cutting adjacentcranial bone to form supporting ledges and the implant was subsequentlyattached by clamping the implant between the ledges and titanium platesand screws. The patient demonstrated a mild local reaction at theoperation site that eventually declined 3-4 days after surgery. Apostoperative CT-scan demonstrated the implant in perfect positioncovering the original bone defect as can be seen in FIGS. 13 a) and 13b). Clinical and radiological follow-up 3 months after surgery show awell-tolerated implant without signs of infection, inflammation orpenetration through the skin. The implant was still intact withoutresorption at this time-point as demonstrated by CT-scans shown in FIGS.13 c) and 13 d).

While the implant was attached using clamps in the above examples it isalso possible to attach it using sutures and a combination of clamps andsutures.

The invention is not limited to the embodiments shown, which can bevaried freely within the framework of the following claims. Inparticular, the features of the various embodiments and examplesdescribed may be freely combined with each other in order to reachadditional embodiments, which are all considered part of the scope ofthe present application.

The invention claimed is:
 1. An implant comprising a plurality ofdiscrete biocompatible molded cement mosaic plates of thickness dconnected by wire arms molded into and extending substantially laterallyfrom the mosaic plates, wherein neighbouring mosaic plates are separatedby a gap of width t.
 2. An implant according to claim 1 wherein at leasttwo neighbouring mosaic plates are joined together by a skin which has athickness s which is less than thickness d.
 3. An implant according toclaim 1 wherein each mosaic plate has a maximum width w which is between2 and 20 millimetres.
 4. An Mosaic implant according to claim 3 whereinthickness d is between 10% and 150% of w.
 5. An implant according toclaim 4 wherein thickness d is between 20% and 130% of w.
 6. An implantaccording to claim 4 wherein thickness d is between 50% and 130% of w.7. An implant according to claim 3 wherein each mosaic plate has amaximum width w between 3 and 15 mm.
 8. An implant according to claim 3wherein each mosaic plate has a maximum width w between 4 and 10 mm. 9.A method of forming an implant according to claim 1, wherein the methodcomprises the steps of moulding a cement composition around a wire ormesh and subsequently allowing said cement composition to cure.
 10. Amethod according to claim 9 comprising the steps of: a) providing amould with a plurality of cavities of depth d, each of which has theshape of a mosaic plate, wherein each cavity has a closable bottom endand is open at the opposite end to allow filling of the cavity, whereineach wall between adjacent cavities is pierced by at least one narrow,wire- or mesh-retaining channel of width ww; b) placing a wire or meshin each wire- or mesh-retaining channel, c) filling said mould cavatieswith a cement composition, and d) allowing said cement to harden.
 11. Amethod according to claim 9 comprising the steps of: i) providing afirst mould half with a plurality of cavities of depth dl, each of whichhas the shape of a mosaic plate, wherein each cavity has a closablebottom end and is open at the opposite end to allow filling of thecavity, ii) filling said first mould half cavities with an excess ofcement composition; iii) placing a wire or mesh over the open ends ofsaid cavities; iv) placing a second mould half which has cavities ofdepth d2 arranged as a minor-image of the first mould half on top of thewire or mesh and compressing it towards the first mould half; and v)allowing said cement to harden.
 12. A method according to claim 9wherein the cement composition is a non-aqueous hydraulic cementcomposition.
 13. A method according to claim 9 wherein the step ofallowing said cement to harden takes place in a wet environment.
 14. Amethod according to claim 9 wherein the step of allowing said cement toharden takes place in a moist environment.
 15. A method of implanting animplant in accordance with claim 1 in a patient, comprising the stepsof: i) exposing at least some of the tissue of the patient surroundingthe area where the implant is to be placed, ii) forming the implant tothe desired shape, iii) attaching the implant to tissue, and iv) closingthe exposure.
 16. A method according to claim 15 wherein the step ofattaching the implant to the tissue is achieved by using sutures and/orclamps and/or screws and/or plates with screws.
 17. An implant accordingto claim 1 wherein the molded cement mosaic plates comprise Monetite.18. An implant according to claim 17, wherein the mosaic platescomprising Monetite are formed from an acidic cement compositioncomprising beta-tricalcium phosphate and monocalcium phosphatemonohydrate.
 19. An implant according to claim 1 wherein each mosaicplate has a maximum width w between 2 and 20 millimeters and thickness dbetween 50% and 130% of w.
 20. An implant according to claim 1, whereineach mosaic plate has a top surface and a bottom surface, and at leastone of top surface and the bottom surface is exposed.
 21. A method ofimplanting an implant in accordance with claim 1 in a patient,comprising the steps of: i) exposing at least some of the tissue of thepatient surrounding the area where the implant is to be placed, ii)attaching the implant to tissue, wherein the implant has been shaped tofit a defect in the tissue, and iv) closing the exposure.
 22. An implantcomprising a plurality of discrete biocompatible hexagonal mouldedcement mosaic plates of maximum width w, wherein w is from 4 to 10 mm,and thickness d, wherein d is from 50% to 130% of w, connected by wirearms moulded into and extending substantially laterally from the mosaicplates, wherein neighbouring mosaic plates are separated by a gap ofwidth t, and t is less than 3 mm, and wherein the mosaic plates compriseMonetite.